Alterations in neurotransmission in central serotonergic systems have been linked to both the pathogenesis of depression and the mechanism of action of antidepressant treatment. We have developed a new paradigm for studying 5-HT function in humans: the clomipramine (CMI) challenge test. By measuring the neuroendocrine response to an intravenous dose of the 5-HT reuptake inhibitor CMI, this test provides a relatively specific index of 5-HT function. In the first two years of this grant, we have found that depressed patients have decreased 5-HT function, as manifested by blunted neuroendocrine responses to CMI. Preliminary data suggest that following pharmacotherapy, the CMI test tends to normalize in depressed patients who respond to treatment, while an opposite pattern is seen in non-responders. The overall goal of our proposed research is to delineate further the role that 5-HT plays in the pathogenesis of depression and in determining the clinical outcome of treatment. We plan to test several specific hypotheses: 1) The abnormal neuroendocrine response to CMI challenge in depressed patients is a manifestation of a biological vulnerability which can be compensated for with antidepressant (i.e., desipramine) treatment, but will re-emerge following treatment discontinuation. We will test this hypothesis in a longitudinal study applying the CMI challenge test to depressed patients prior to the initiation for treatment with desipramine, after 6 weeks of treatment, at the end of treatment, and again 6 weeks after treatment discontinuation in a drug-free, state of remission. 2) Desipramine exposure will not enhance the neuroendocrine response to CMI in healthy subjects, nor in depressed patients who prove to be antidepressant non-responders. We will study the effects of desipramine exposure on the CMI challenge test in healthy subjects, and will also compare post- treatment CMI test results in patients who are non-responders to those of responders. 3) The mechanisms responsible for the blunted neuroendocrine response to CMI in depressed patients include decreased pre-synaptic 5-HT availability. We will test this hypothesis by decreasing pre-synaptic 5-HT stores in healthy volunteers via acute tryptophan depletion. We predict that this will lead to a CMI response profile that will mimic the pattern seen in depressed patients. 4) A single exposure to a 5-HT reuptake inhibitor can lead to long-term functional receptor changes. We predict that two weeks following a single exposure to CMI, the prolactin, ACTH, and growth hormone responses to a second CMI challenge will become blunted in normal subjects; these neuroendocrine responses to CMI challenge will return to baseline after 4 weeks. These studies will provide important clarification of the role that 5-HT plays in the pathogenesis of depression and in determining the clinical outcome of treatment with the tricyclic antidepressant desipramine.